New approaches are needed to improve cure rates in adult hematological malignancies. PPARgamma (Peroxisome Proliferator-Activated Receptor Gamma) is a member of the nuclear transcription factor family involved in signaling of differentiation. We have demonstrated that PPARgamma is expressed in the majority of primary human leukemias but not in normal hematopoietic progenitors, and that ligation of PPARgamma induces differentiation, growth arrest and apoptosis in leukemias. We propose to extend our initial studies on the mechanisms and efficacy of PPARgamma signaling in acute myeloid leukemia to acute and chronic (CLL) leukemia, with the goal of developing PPARgamma as a novel target for the treatment of hematological malignancies. We are encouraged to pursue this goal by the seminal impact on leukemia therapy that was affected by targeting RARalpha in acute promyelocytic leukemia (APL) with ATRA. First, we will investigate the expression of PPARgamma, in acute and chronic myeloid and lymphoid human leukemias and leukemic stem cells and study the effects of PPARgamma ligands on apoptosis and differentiation. We will determine the effects of combined targeting of PPARgamma and RXR in leukemias, as PPARgamma, and RXR heterodimerization is required to maximize transcriptional activation. In the second aim, we will further elucidate the specific mechanisms of apoptotic cell death and growth arrest that are triggered by PPARgamma, ligation. Preliminary data demonstrate that PPARgamma ligands induce loss of mitochondrial membrane potential and activation of effector caspases. Finally, we propose to initiate Phase I studies using PPARgamma ligands, in combination with rexinoids. These studies will utilize FDA approved PPARgamma and RXR ligands and the new potent triterpenoid CDDO, a novel PPARgamma, ligand that is presently being developed by us with assistance from CTEP/RAID at the National Cancer Institute. The long-term goal of the proposed studies is to determine the molecular, biological and clinical effects of PPARgamma/RXR ligation in human leukemia and to develop the PPARgamma/RXR nuclear receptor system as a novel target for leukemia therapy.